Educational Case: Renal allograft rejection.

Chronic rejection, the slowest presenting form of transplant rejection, typically manifests in the timespan of months to years. The pathogenesis of chronic rejection involves either cell- or humoral-mediated processes that involve memory cells, plasma cells, and antibody production against donor antigens. The findings of chronic rejection are nonspecific and include interstitial fibrosis and tubular atrophy with associated interstitial inflammation, vascular changes characterized by thickened intima containing macrophages and lymphocytes, and transplant glomerulopathy with mesangial matrix expansion and double contour of capillary walls.9.

COVID-19 Associated Collapsing FSGS in an APOL1 Homozygous Transplant Recipient After Successful COVID Vaccination: A Case Report.

Organ transplant recipients exhibit lower rates of immune response to coronavirus disease 2019 (COVID-19) vaccination. Even when they do mount a demonstrable antibody response, it is unclear what degree of protection is conferred against the myriad potential complications of COVID-19 infection. We present here a case of a kidney transplant recipient who was homozygous for APOL1 risk alleles on low-dose immunosuppression who developed an antibody response to COVID-19 vaccination and subsequently acquired COVID-19 infection. Although she experienced relatively minor effects in other organ systems, she developed severe collapsing focal segmental glomerulosclerosis that left her dependent on hemodialysis on hospital discharge. This suggests that COVID-19 vaccination may not provide protection from infection-associated focal segmental glomerulosclerosis in patients with APOL1 risk alleles.

Assessment of the Banff Working Group classification of definitive BK polyomavirus nephropathy.

Polyomavirus associated nephropathy (PyVAN) continues to be a burden in renal transplantation leading to allograft insufficiency or graft failure. A presumptive diagnosis of PyVAN is made based on the presence of BK polyomavirus in patients' plasma; however, kidney biopsy remains the gold standard to establish a definitive diagnosis. The Banff Working Group on PyVAN proposed a novel classification of definitive PyVAN based on polyomavirus replication/load level and the extent of interstitial fibrosis. The aim of our study was to test the newly defined classes of PyVAN using independent cohorts of 124 kidney transplant patients with PyVAN with respect to the initial presentation and outcome, and to compare our analysis to that previously reported. Detailed analysis of our cohort revealed that the proposed classification of PyVAN did not stratify or identify patients at increased risk of allograft failure. Specifically, while class 3 was associated with the worst prognosis, there was no significant difference between the outcomes in classes 1 and 2. We also found that the timing post-transplantation and inflammation in areas of interstitial fibrosis and tubular atrophy might be additional factors contributing to an unfavorable allograft outcome in patients with PyVAN.

Diagnostic role of technitium-99m bone scan in severe COVID-19-associated myositis.

Coronavirus disease 2019 (COVID-19), initially appreciated as a respiratory illness, is now known to affect many organs in the human body. Significant data has become available on muscle involvement, with creatinine kinase elevations present in a significant percentage of patients. For those with suspected COVID-19-associated myositis, the imaging modality of choice has been gadolinium-enhanced magnetic resonance imaging; however, the use of technitium-99 m bone scan has not been previously reported. Here, we report two cases of COVID-19 patients with severe elevation in creatinine kinase who underwent technitium-99 m bone scan. The resulting images showed diffuse symmetrical muscle involvement. Both patients developed acute renal injury due to rhabdomyolysis. To our knowledge, this is the first report of bone scan as a diagnostic imaging modality for COVID-19-associated myositis.

Early Transplant Arteriopathy in Kidney Transplantation.

BACKGROUND: Early dysfunction of renal allografts may be associated with vascular injury, which raises the specter of active rejection processes that require medical intervention. In our practice, we have encountered patients who present with delayed graft function and demonstrate a unique pattern of endothelial cell injury that raises concern for rejection in their biopsy. Therefore, we sought to systematically determine the biopsy characteristics and outcome of these patients. METHODS: During a 17-year period at the University of Washington in Seattle, United States, we identified 24 cases of a distinct arterial vasculopathy presenting in the first year posttransplantation. This early transplant arteriopathy (ETA) is characterized by endothelial cell swelling and intimal edema but without the intimal arteritis that defines vascular rejection. RESULTS: Approximately 1% of transplant biopsies during the study period showed ETA, almost all of which were in deceased donor organs (96%), and most presented with delayed graft function (54%) or increased serum creatinine (38%) soon after transplantation (median 13 days; range, 5-139). In this study, 77% of patients were managed expectantly, with only 2 patients (7.6%) subsequently developing acute vascular rejection. Except for 1 patient who died, all patients had functioning allografts at 1 year follow-up. CONCLUSION: Recognizing ETA and distinguishing it from vascular rejection is important to prevent over-treatment because most patients appear to recover allograft function rapidly with expectant management.

Educational Case: Giant Cell Tumor of the Bone in Both the Axial and Appendicular Skeleton.

The following fictional case is intended as a learning tool within the Pathology Competencies for Medical Education (PCME), a set of national standards for teaching pathology. These are divided into three basic competencies: Disease Mechanisms and Processes, Organ System Pathology, and Diagnostic Medicine and Therapeutic Pathology. For additional information, and a full list of learning objectives for all three competencies, see http://journals.sagepub.com/doi/10.1177/2374289517715040.1.

Fibrilo-Tactoid Glomerulonephritis: A Possible Novel Morphological Variant.

Fibrillary and immunotactoid glomerulonephritis are infrequent causes of primary nephrotic range proteinuria and are poorly understood. Recent significant developments include the discovery of DNA JB9 antigen in fibrillary glomerulonephritis. Here, we present a case of a middle-aged woman who presented with nephrotic range proteinuria, hematuria, and normal renal function. Renal biopsy revealed fibrils that were randomly arranged on electron microscopy. They were of small size and congo red negative similar to the ones found in fibrillary glomerulonephritis, but were also DNA JB 9 negative, and had a hollow core like in immunotactoid glomerulopathy. Though we try to classify these conditions into either immunotactoid glomerulonephropathy (ITGN) or fibrillary glomerulonephritis (FGN), there are scenarios such as this case where it does not fit into either and is probably an overlap or intermediate variant of these two conditions. Pathological features of these glomerulonephrites are discussed together with their clinical implications, treatment choices, and diagnostic importance.

Previously Unidentified Gene Variation Associated with Fabry Disease: The Impact on One Family.

Fabry disease is an X-linked lysosomal storage genetic disorder associated with over 1000 mutations in the alpha-galactosidase-A gene region. We report here a 69-year-old male who underwent a kidney biopsy to evaluate progressive renal failure. He was found to have zebra bodies in visceral epithelial cells on biopsy, with electron microscopy showing inclusions within the cytoplasm of multiple podocytes consistent with Fabry disease. An alpha-galactosidase level was found to be 21 nm/hr/mg (normal range 50-150 nm/hr/mg). Genetic studies revealed a missense variant in the GLA gene with alanine replaced by cysteine at position 682 (c.682 A > C, p.N228H) that had not been previously associated with Fabry disease. The same variant was detected in two additional family members. The pathologic findings, clinical features, and low alpha-galactosidase level suggest that the c.682 A > C variant is associated with Fabry disease.

Educational Case: Nephrotic Syndrome in Older Adult.

The following fictional case is intended as a learning tool within the Pathology Competencies for Medical Education (PCME), a set of national standards for teaching pathology. These are divided into three basic competencies: Disease Mechanisms and Processes, Organ System Pathology, and Diagnostic Medicine and Therapeutic Pathology. For additional information, and a full list of learning objectives for all three competencies, see http://journals.sagepub.com/doi/10.1177/2374289517715040.1.

Corrigendum to "Pericardial Tamponade: An Uncommon Clinical Presentation in cANCA Related Vasculitis and Glomerulonephritis in Association with Very High Titres of ANA".

[This corrects the article DOI: 10.1155/2019/4983139.].

Pericardial Tamponade: An Uncommon Clinical Presentation in cANCA Related Vasculitis and Glomerulonephritis in Association with Very High Titres of ANA.

ANCA (anti-neutrophil cytoplasmic antibody) vasculitides are systemic autoimmune diseases in which anti-neutrophilic cytoplasmic antibodies activate primed neutrophils, thereby generating an inflammatory cascade resulting in the damage of small sized blood vessels in various organs of the body, including the heart. Pleuropericardial involvement is underrecognized as a complication of ANCA vasculitis and is highlighted in this case report of a 51-year-old male who presented with an initial symptomatic presentation of pleuropericardial effusion progressing to pericardial tamponade in the setting of a later renal biopsy proven pauci-immune crescentic glomerulonephritis with high ANA titres along with positive cANCA (cytoplasmic ANCA) and PR3 (proteinase 3) antibodies. He was found to have acute renal failure which progressively got better with cyclophosphamide.

Transplantation With APOL1 Risk Variant Kidney May Be Associated With Lifetime Risk for Recurrence of Focal Segmental Glomerulosclerosis: A Case Report and Review of Literature.

The APOL1 gene mutation is increasingly recognized as an import factor in living kidney donation. APOL1 gene variants prevalent in the African American population have been associated with increased risk of glomerulopathy. Shorter allograft survival is seen in transplants from donors who had 2 risk APOL1 gene alleles. In the early posttransplant period, kidneys with 2 risk alleles of APOL1 had higher risk of graft loss compared to 1 or 0 risk alleles, but by year 4 of transplant it was almost similar. The authors have suggested that recipients of kidney transplants with 2 risk alleles may only be at risk for kidney failure during the early initial period. We present here a case of a patient with 2 risk APOL1 alleles who received renal transplant from her identical twin and developed glomerulopathy 18 years after the transplant. No case of APOL1-associated recurrent glomerulonephritis has been described in a recipient after 10 years. This suggests that the risk of recurrence of glomerulopathy in allograft transplants with 2 risk allele variants may not be limited to the initial post-transplant period; rather, it may be a lifetime risk.

ANCA-Associated Vasculitis Co-Occurrence With Systemic Sclerosis: A Case Report of a Rare Diagnostic Dilemma.

Systemic sclerosis (SSc) is a rare autoimmune disorder that is typically divided into limited cutaneous systemic sclerosis and diffuse cutaneous systemic sclerosis. Scleroderma renal crisis (SRC) is a severe complication of SSc and typically presents with new-onset hypertension and a reduction in renal functioning. In patients presenting with typical features of SRC, treatment with an angiotensin-converting enzyme inhibitor along with dialysis as needed is typically initiated empirically. Renal biopsy is not recommended in patients with SSc presenting with typical features of SRC. Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a rare co-occurrence with SSc, in around 2.5% to 9% of patients. AAV is an inflammatory condition that can result in renal failure due to mononuclear cell infiltration and destruction of blood vessels. Treatment of AAV is drastically different from SRC and typically consists of immunosuppressants and dialysis if needed. SRC and AAV can only reliably be distinguished by renal biopsy. We present a rare case of a 70-year-old female with limited cutaneous systemic sclerosis who presented to the emergency department with new-onset renal failure. Her serology was found to be positive for antinuclear antibodies and myeloperoxidase antibodies, resulting in a renal biopsy, which revealed an acute necrotizing vasculitis consistent with AAV. We suggest consideration of a renal biopsy in patients with SSc who present with new-onset renal failure, especially with nonresponse to SRC treatment or positive serology.

Single center experience of subclinical rejections and BK nephropathies by kidney allografts' surveillance biopsies.

PURPOSE: Acute rejection of the kidney allograft remains the most important factor affecting the long-term graft outcome and is a major predictor of development of chronic damage and graft loss. Several studies have shown that early detection and treatment of subclinical rejection episodes may be beneficial for the graft outcome. The role of protocol (surveillance) biopsies and the value of donor specific antibodies (DSA) monitoring are still debatable. METHODS: This is a prospective observational study involving seventeen kidney recipients transplanted in north-eastern part of Poland who underwent "zero", 3-month and 12-month allograft biopsies as well as DSA assessment. RESULTS: Histologic analysis of the biopsies showed subclinical acute cellular rejection in 17.6% of patients (two tubulointerstitial, one vascular) at 3-months post transplantation, and additional case of borderline rejection at the 12-month point. Moreover, two cases (11.8%) of polyomavirus BK nephropathy were diagnosed (one at 3 and one at 12 month point). None of the patients developed de novo DSA. CONCLUSIONS: Our protocol biopsies allowed us to detect significant proportion of patients with subclinical, but histologically relevant acute cellular rejection and BK nephropathy. Early therapeutic intervention had beneficial effects in a 4-year follow up.

Clinicopathologic correlations of renal pathology in the adult population of Poland.

BACKGROUND: This is the first report on the epidemiology of biopsy-proven kidney diseases in Poland. METHODS: The Polish Registry of Renal Biopsies has collected information on all (n = 9394) native renal biopsies performed in Poland from 2009 to 2014. Patients' clinical data collected at the time of biopsy, and histopathological diagnoses were used for epidemiological and clinicopathologic analysis. RESULTS: There was a gradual increase in the number of native renal biopsies performed per million people (PMP) per year in Poland in 2009-14, starting from 36 PMP in 2009 to 44 PMP in 2014. A considerable variability between provinces in the mean number of biopsies performed in the period covered was found, ranging from 5 to 77 PMP/year. The most common renal biopsy diagnoses in adults were immunoglobulin A nephropathy (IgAN) (20%), focal segmental glomerulosclerosis (FSGS) (15%) and membranous glomerulonephritis (MGN) (11%), whereas in children, minimal change disease (22%), IgAN (20%) and FSGS (10%) were dominant. Due to insufficient data on the paediatric population, the clinicopathologic analysis was limited to patients ≥18 years of age. At the time of renal biopsy, the majority of adult patients presented nephrotic-range proteinuria (45.2%), followed by urinary abnormalities (38.3%), nephritic syndrome (13.8%) and isolated haematuria (1.7%). Among nephrotic patients, primary glomerulopathies dominated (67.6% in those 18-64 years of age and 62.4% in elderly patients) with leading diagnoses being MGN (17.1%), FSGS (16.2%) and IgAN (13.0%) in the younger cohort and MGN (23.5%), amyloidosis (18.8%) and FSGS (16.8%) in the elderly cohort. Among nephritic patients 18-64 years of age, the majority (55.9%) suffered from primary glomerulopathies, with a predominance of IgAN (31.3%), FSGS (12.7%) and crescentic GN (CGN) (11.1%). Among elderly nephritic patients, primary and secondary glomerulopathies were equally common (41.9% each) and pauci-immune GN (24.7%), CGN (20.4%) and IgAN (14.0%) were predominant. In both adult cohorts, urinary abnormalities were mostly related to primary glomerulopathies (66.8% in younger and 50% in elderly patients) and the leading diagnoses were IgAN (31.4%), FSGS (15.9%), lupus nephritis (10.7%) and FSGS (19.2%), MGN (15.1%) and pauci-immune GN (12.3%), respectively. There were significant differences in clinical characteristics and renal biopsy findings between male and female adult patients. CONCLUSIONS: The registry data focused new light on the epidemiology of kidney diseases in Poland. These data should be used in future follow-up and prospective studies.

Kidney Biopsies May Help Predict Renal Function After Liver Transplantation.

BACKGROUND: Renal biopsy has been proposed to determine the cause or reversibility of renal failure for patients with end-stage liver disease and may be useful in the kidney allocation. Nevertheless, little data exist to validate the usefulness of kidney biopsies in this patient population. METHODS: We evaluated the utility of renal biopsies in a cohort of 59 consecutive liver transplant candidates with renal impairment of unclear etiology referred to determine the need for simultaneous liver kidney transplantation (SLK) versus liver alone transplantation (LAT). Pathological diagnoses, patient outcomes and the usefulness of biopsy results in predicting renal recovery were analyzed. RESULTS: Our biopsy complication rate was relatively low with only 2.9% and 4.2% serious complications occurring with transjugular and percutaneous renal biopsies, respectively. The most common pathological diagnoses on renal biopsies were membranoproliferative glomerulonephritis (23%) followed by IgA nephropathy (19%) and acute tubular injury (19%). Simultaneous liver kidney transplantation was recommended for patients with greater than 40% global glomerular sclerosis, or with interstitial fibrosis greater than 30% or for patients on hemodialysis for 2 months or longer. The best histological predictor for posttransplant glomerular filtration rate in the LAT group was the extent of global glomerulosclerosis (P = 0.0001). Based on biopsy criteria, we were able to avoid kidney allocation to 70% of our patients with renal dysfunction. Over the first year posttransplant, SLK and LAT patients had comparable estimated glomerular filtration rates. Kaplan-Meier survival analysis did not demonstrate a difference in patient survival between patients who underwent LAT versus SLK. CONCLUSIONS: Renal biopsy can be relatively safe in this population, may help elucidate the etiology of renal failure, may predict post-LAT kidney function, and may be helpful in kidney allocation for liver transplant candidates.

Pathology of recurrent diseases in kidney allografts: membranous nephropathy and focal segmental glomerulosclerosis.

PURPOSE OF REVIEW: Glomerulonephritis is the leading cause of end-stage renal failure in renal transplant recipients. Recurrence of diseases in kidney allograft provides a unique opportunity to study the mechanisms of kidney disorders leading to the underlying native organ failure. There have been new advances in the understanding of the mechanisms of membranous nephropathy and focal segmental glomerulosclerosis (FSGS). RECENT FINDINGS: Recent studies of recurrent membranous nephropathy provide evidence of the presence of circulating recipient factor that targets the donor kidney and put forward the evidence of antiphospholipase A2 receptor antibody pathogenicity in some cases, point to a different pathogenesis of recurrent and de-novo membranous nephropathy, and stress the importance of early morphologic recognition of recurrent membranous nephropathy. New advances in understanding the FSGS include identification of soluble podocyte urokinase receptor as a circulating factor leading to the development and recurrence of FSGS after transplantation, imply that podocyte injury may be a reversible lesion, and suggest a dual role of activated parietal epithelial cells in sclerosing glomerular injury as well as in regeneration and repair. SUMMARY: Several new mechanisms of glomerular injury have been implicated in the development of recurrent kidney diseases. When further confirmed, some of these might result in early diagnosis and development of better therapy of the respective disorders.

Expression of estrogen receptors α and ß in paratesticular tissues in boys operated on for unilateral cryptorchidism between the 1st and 4th years of life.

BACKGROUND: The aim of this study was to assess the expression of estrogen receptors alpha and beta in paratesticular tissues in a group of boys with and without cryptorchidism, and evaluation of karyotypes, localization, morphology and the major length of the undescended testes. MATERIAL/METHODS: Fifty boys (1-4 years old) with unilateral cryptorchidism were evaluated. Fifty healthy boys within the same age range, with inguinal hernia, served as a control group. Measurements concerning expression of ERalpha ERbeta receptors were preformed using monoclonal mouse antibodies against human receptor alpha and beta. RESULTS: In the mesothelial layer, the expression of ERalpha was higher in the patients group with undescended testes and it was statistically significant (p=0.04). There was no difference in the expression of ERbeta in this layer between groups. In the stromal cell layer there was statistically significant higher expression of ERbeta (p<0.05) in the group of patients with undescended testes. CONCLUSIONS: There was no difference between expressions of ERalpha in stromal cell layer. In the endothelial layer there was no difference in expression of ERalpha and ERbeta. In the smooth muscle layer there was no expression of ERalpha in either group. The expression of ERbeta in the smooth muscle layer was nearly identical in both groups. Undescended testes were generally found in the superficial inguinal pouch (n=46). The major lengths of the undescended testes were smaller in comparison to the testes positioned normally. In 9 of the cases the testes had different shape, and turgor deficit, and epididymides were smaller, dysplastic and separated from the testis.

Patterns of glomerular injury in kidneys infiltrated by lymphoplasmacytic neoplasms.

Glomerular injury may occur as a result of immune dysfunction in patients with remote lymphoplasmacytic neoplasms. Glomerular injury concurrent with direct infiltration of the kidney by lymphoplasmacytic neoplasms has been reported but is not extensively characterized. We identified 18 patients, all presenting with elevated serum creatinine and many with proteinuria, whose renal biopsies showed direct involvement of kidney by a variety of neoplasms, including chronic leukocytic leukemia/small lymphocytic lymphoma (n = 7), diffuse large B-cell lymphoma (n = 6), multiple myeloma (n = 4), or B-cell lymphoblastic lymphoma (n = 1). In 10 cases (55%), there was coexistent glomerular pathology: 5 of these cases, including glomerulonephritis with membranoproliferative glomerulonephritis-like pattern of injury (n = 4) and membranous nephropathy (n = 1), featured deposition of immune complexes; 2 demonstrated deposition of monoclonal immunoglobulin components: λ light chain amyloidosis (n = 1) and light chain deposition disease (n = 1); 2 showed minimal change disease; and, in 1 case, there was focal crescentic pauci-immune-type glomerulonephritis. In addition, 1 biopsy revealed diabetic nephropathy and 3 showed nonspecific ischemic changes. In the remaining 4 cases, there were no significant glomerular abnormalities. In 11 cases (61%), the diagnosis of lymphoproliferative disease was established following the kidney biopsy. Our study indicates that lymphoplasmacytic neoplasms may be first diagnosed in renal biopsies performed for evaluation of renal dysfunction with or without proteinuria. Concurrent glomerular injury may be a direct result of the lymphoplasmacytic disorder through a paraprotein deposition process resulting in amyloid or monoclonal immunoglobulin deposition disease, or may be caused indirectly through immune-mediated mechanisms, as in the cases of glomerulonephritis with membranoproliferative glomerulonephritis-like pattern of injury, membranous nephropathy, and possibly minimal change disease.